GB2153354A - Novel therapeutically active compounds of the formula - Google Patents

Abstract

Novel therapeutically active compounds of the formula <CHEM> wherein Z , being Z<1>, Z<2> or Z<3>, is the same or different and selected among OH, OR<1>, NH2, NR2<4>, NHR<4>, SH, SR<4> and OR<4> wherein R<1> is a formyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkylcarbamoyl group and R<4> is a lower alkyl group, R<2> is a hydrogen, a halogen, a lower alkyl or a lower trifluoroalkyl group, R<3> is a hydrogen atom, a lower alkyl group, an alkenyl group, an alkynyl group or a phenyl group, which phenyl group could optionally be substituted by one or more of fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy or ethoxy in the ortho, metal or para positions, or optionally substituted by methylenedioxy, provided that at least one of Z<1>, Z<2> and Z<3> is a group OR<4> and further provided that when Z<2> is OH or NH2, Z<1> is NR2<4>, NHR<4>, SH, SR<4> or OR<4> or a physiologically acceptable salt or optical isomer thereof, intermediates and methods for their preparation, pharmaceutical preparations containing the compounds and methods for their therapeutical use.

Description

1 GB 2 153 354A 1

SPECIFICATION

Oxysalicylamido derivatives Field of the Invention The present invention relates to novel, pharmacologically active derivatives of oxy-substituted salicylamides, intermediates and processes for their preparation, pharmaceutical compositions containing the oxy-salicylamidoderivatives and to methods of their pharmacological use.

The object of the invention is to provide a substituted benzamide neuroleptic useful for the blockade of dopamine receptors in the brain. Such substances will be useful in the treatment of 10 emesis, anxiety states, psychosomatic diseases and psychotic states, such as schizophrenia and depression, alcoholic related diseases, confusional states and sleep disturbances in the elderly.

Prior Art

Remoxipride (U.S. Patent No. 4 232 037) with the formula Br OCH 3 CONHCH 2 N 1 OCH 3 c 2 H 5 is a recently developed antipsychotic agent. This compound is claimed to be a potent antagonist of the apomorphine syndrome in the rat.

In European Patent Application No. 60235 benzamido derivatives claimed to be potent 25 inhibitors of the apomorphine syndrome in the rat, are disclosed, among these the compound of the formula cl ' OH 5-/' F- CONHCH 2 N 1 cl OCH 3 c 2 H 5 The compounds of U.S. 4 232 037 and EP 60235 have less potent antidoparninergic effects 35 than the compounds of the present invention.

Disclosure of the Invention

The present invention relates to compounds of the formula zj R 2 Z 1 CONHCH 2 N Z 2 1 3 CH 2 R 1 wherein Z1, being Z1, Z1 or Z-1, is the same-or different and selected among OH, OW, NH2, NR 4 4, 2, NHR SH, SR 4 and OR 4 wherein R' is a formy] group, an acyl group, an alkoxycarbonyl group or a 50 mono- or dialkylcarbamoyl group and R 4 is a lower alkyl group, R 2 is a hydrogen, a halogen, a lower alkyl or a lower trifluoroalkyl group, R 3 is a hydrogen atom, a lower group, an alkenyl group, an alkynyl group or a phenyl group, which phenyl group could optionally be substituted by one or more of fluoro, chloro, bromo, trif 1 uoro methyl, methyl, ethyl, methoxy or ethoxy in the ortho, meta or para positions, or 55 optionally substituted by methylenedioxy; provided that at least one of Z1, Z2 and Z3 is a group OR 4 and further provided that when Z2 is OH or NH2, Z1 is NR 4 4, 4 4 2, NHR SH, SR or OR or a physiologically acceptable salt or optical isomer thereof.

It has been found that such compounds have valuable therapeutical properties, particularly they have more potent antidopaminergic effects than the prior art compounds discussed above 60 and they also exhibit a larger separation to drug induced extrapyramidal side effects.

The invention thus provides compounds, and physiologically acceptable salts thereof, which compounds are useful in therapeutic treatment of emesis, anxiety states, psychosomatic diseases such as gastric and duodenal ulcer, and psychotic states such as schizophrenia and depression, alcoholic related diseases, confusional states and sleep disturbances in the elderly.

2 GB 2 153 354A 2 Halogen atoms in formula 1 comprise chlorine, bromine, fluorine and iodine atoms.

Lower alkyl groups in formula 1 are straight or branched alkyl groups with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i- butyl and t-buty].

Lower trifluoroalkyl group in formula 1 is a group F3C-(CHI- wherein n is 0, 1 or 2.

Alkenyl groups in formula 1 are straight or branched hydrocarbon chains with 2 to 3 carbon atoms and a double bond, such as vinyl, allyl or isopropenyl.

Alkynyl groups in formula 1 are hydrocarbon chains with 2 to 3 carbon atoms with a triple bond, that is -C=-CH3, -CH2-C=-CH3 and -C=-CCH, Acyl groups in formula 1 are alkyl-CO- where the alkyl moiety is a straight or branched hydrocarbon chain with 1 to 17 carbon atoms, preferably 1 carbon atoms.

Alkoxycarbonyl groups in formula 1 are alkyl-O-CO wherein the alkyl moiety is a hydrocarbon chain with 1 - 17 C as defined above, preferably 1 C.

Monoalkylcarbamoyl groups in formula 1 are groups alky]-NH-CO- wherein the alkyl moiety is a hydrocarbon chain with 1 - 17 C as defined above, preferably 1 - 15 C.

Dialkylcarbamoyl groups in formula 1 are groups alkyl' alky 12 N-CO20 wherein the alkyll and alky 12 can be the same or different and each is a hydrocarbon chain with 1 - 17 C as defined above, preferably 1 - 15 C.

Phenyl substituted with methylenedioxy in formula 1 is the group 0", C:o CH 2 or 1 11,,\ / 0 0 -CH 2 Compounds of the formula 1 A below are failing within the general scope of the invention:

R 2 OA 1 CONHCH 2 N A 3_Z./ OA 2 1 3 CH 2 -R 1 - wherein A 3 is a hydrogen atom, or a lower alkyl group, R' is a hydrogen atom, a halogen atom, a lower alkyl group or a lower trifluoroalkyl group, Z is a moiety selected among oxygen, sulphur, nitrogen and alkyl- substituted nitrogen, 45 A' is a hydrogen atom, a lower alkyl group, a formyl group, an acyl group, an alkoxycarbonyl 45 group or a mono- or di- alkylcarbamoyl group, A' is a methyl or an ethyl group, R3 is a hydrogen atom, a lower alkyl group, an alkenyl group, an alkynyl group or a phenyl group, which phenyl group could optionally be substituted by one or more of fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy in the ortho, meta or para positions, or optionally 50 substituted by methylenedioxy, or a physiologically acceptable salt or optical isomer thereof.

Preferred groups of compounds of the invention is obtained when in formula 1 a) ZI, ZI and Z3 is OH, 0Me, OEt, 0-acyl, NH, NHMe, NHEt, NMe, and NEt, with one or more of Z, ZI and Z3 being 0Me or OEt, R' is Cl, Br, 1, Me, Et, Pr, R' is hydrogen, methyl, 55 ethyl, vinyl, ethynyl or substituted phenyl group, or b) Z1, Z2 and Z3 is OH, 0Me, OEt, 0-acyl and NH2 with one or more of Z being 0Me or OEt, R 2 is Cl, Br, Et, Pr R3 is as in a), or C) Z1, Z2 and Z3 is OH, 0Me and 0-acyl with one or more of Z'being 0Me, R 2 is Cl, Br, Et, Pr R3 is methyl, ethyl, vinyl or substituted phenyl, or d) Z' is OH or 0-acyl Z2 and Z3 is 0Me R 2 is Cl, Br, Et, Pr 3 GB 2 153 354A 3 R3 is methyl or vinyl and the configuration of the pyrrolidine ring being S (sinister) or phenyl or para-halogen substituted phenyl and the configuration of the pyrrolidine ring being R (rectus). Compounds particularly preferred are B] OH CORCH 2 J H3C0 OCH3 L2MS Br OH 1 1-11 -CONHCH N 2 1 CH2CH=CH 2 1 LtY OCH3 10 Cl \--/OH Br OH z7, CONHCH - J / \ - CONHCH 2 --", N 2 N CH H3C0 OCH3 HS CH30 OCH3 2 15 H SC2 OH CONHCH2 H 3 CO OCH 3 c 2 H 5 1 0 11 Br OC-(CH 2)14-CH3 CONHCH 2_\ 1 CH 30 OCH 3 c 2 H 5 The new compounds of this invention may be used therapeutically as the racemic mixtures of 25 +)- and ( -)-forms, which are obtained by synthesis. They may also be resolved into the corresponding enantiomers which, likewise, may be used in therapy. The ( + )- and ( -)-forms may also be obtained by the reaction of the corresponding enantiomeric 2aminomethylpyrroli dine derivative with the benzoic acid moiety.

The compounds of this invention may be administered in the form of free bases or their salts 30 with non-toxic acids. Some typical examples of these salts are the hydrobromide, hydrochloride, phosphate, sulphate, sulphonate, sulphamate, citrate, lactate, maleate, tartrate and acetate.

Pharmaceutical preparations In clinical practice the compounds of the present invention will normally be administered 35 orally, rectally or by injection in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable nontoxic, acid addition salt, e.g. the hydrobromide, hydrochloride, phosphate, sulphate, sulphonate, sulphamate, citrate, lactate, maleate, tartrate, acetate and the like in association with a pharmaceutically acceptable carrier. Accordingly, terms relating to the novel compounds of this invention whether generically 40 or specifically are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept.

The carrier may be a solid, semisolid or liquid diluent or capsule. These pharmaceutical preparations constitute a further aspect of this invention. Usually the active substance will 45 constitute between 0.1 and 99 % by weight of the preparation, more specifically between 0.5 and 20 % by weight for preparations intended for injection and between 2 and 50 % by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid pulverulent carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn start or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum, 55 titanium dioxide, and the like.

Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.

For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelatine and for example, glycerol or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatine capsules may contain granulations of the active substance in combination with solid, powder carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or 4 GB 2 153 354A 4 gelatine.

Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral application may be in the form of syrups or suspensions, for 5 example solutions containing from about 0.2 to about 20 % by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxym ethylcel 1 u lose as a thickening agent.

Solutions for parenteral applications by injection can be prepared in an aqueous solution of a 10 water-soluble pharmaceutical ly acceptacle salt of the active substance preferably in a concentra tion of from about 0.5 to about 10 % by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

Compounds of the formula 1 wherein R' is an acyl group, an alkoxycarbonyl group or a mono- 15 or dialkylcarbamoyl group may advantageously be used in pharmaceutical preparations intended for intramuscular administration in order to obtain a sustained release effect, that is a depot effect.

Suitable daily doses for oral administration of the compounds of this invention are 1 -50 mg, preferably 5-20 mg.

Methods of preparation The compounds of the invention may be obtained by one of the following methods. A. The compounds of the formula 2 1 1 1 1 CONHCH - ', n11 - 2 I N Z Z 2 3 CH 2 R 30 wherein Zi, being Z', Z2 or Z3, is the same or different and selected among OH, OW, NH2, NRI, SH, 2 SRI and OW, wherein R' is a formyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkylearbornyl group and R 4 is a lower alkyl group, R2 is a hydrogen, a halogen, a lower alkyl or a lower trifluoroalkyl group, R3 is a hydrogen atom, a lower alkyl group, an alkenyl group, an alkynyl group or a phenyl group, which phenyl group could optionally be substituted by one or more of fluoro, chloro, bromo. trifluoromethyl, methyl, ethyl, methoxy or ethoxy in the ortho, meta or para positions, or optionally substituted by methylenedioxy; provided that at least one of Z', Z2 and Z3 is a group OR 4 and further provided that when Z2 is OH or NH2, Z' is N R4 4, 4 4, 2, NHR SH, SR or OR can be obtained by reaction of a compound of the formula R 2 Z 1 C0-X 1 3 wherein Z1, Z2, Z1 and R 2 have the above given definitions and -CO-Xl is a reactive group capable of reacting with an amino group under formation of an amide moiety, with a compound of the formula 55 H 2 N-CH 2-N CH 2 -R 3 wherein R 3 has the above given definition, or a reactive derivative thereof.

The reaction is carried out in a suitable solvent, such as diethyl ether, THF, dichloromethane, chloroform or toluene between - 2WC and the boiling point of the reaction mixture. The resulting amine can be isolated as a salt recovered e.g. by filtration. Alternatively, the amine obtained can be converted to the free base using conventional techniques, such as the addition of aqueous ammonia or a sodium hydroxide solution, and extraction with an organic solvent. 65 GB 2 153 354A 5 X' in the acylating group -CO-Xl may be a halogen group, such as chlorine or bromine, a mixed anhydride with inorganic acids or their esters, e.g. phenyl phosphate, a thio group, an organic residue, or a hydroxy group in combination with a coupling agent or reactive amine derivative.

The organic residue comprises groups which can form reactive acid derivatives. These can be 5 aliphatic esters, e.g. methyl, ethyl, cyanomethyl or methoxymethyl esters, Whydroxyimide esters or substituted or unsubstituted aromatic esters; acyl nitrile; acyl azide; symmetrical anhydrides; mixed anhydrides; or azolides, e.g. triazolide, tetrazolide or imidazolide.

According to the invention the following compounds can be used as reactive derivatives of the cyclic amine above:

Reaction products 9f the amine with phosphorus chloride, phosphorus oxychloride, dialkyl, diaryl or o-phenylenechlorophosphites or alkyl or aryidichlorophosphites, or an isothiocyanate or isocyanate of the amine. The mentioned reactive derivatives can be reacted with the acid in situ or after previous isolation.

It is also possible to react the free acid and the free amine in the presence of a condensating 15 agent, e.g. silicon tetrachloride, diphosphoruspentoxide, a phosphine or h exa methyl phosphorous triamide plus a carbon tetrahalide, diphenyl phosphite, N-ethoxycarbony]-2-ethoxy-1,2-dihydroquinoline, titanium tetrachloride, or carbodiimides such as dicyclohexylcarbodiimide, KWcarbonyidiimidazole, N,N-thionyidiimidazole and diethyidiazodicarboxylate.

B. The compounds of the formula 1, wherein R 2 and R3 are as defined in A and Z1, Z2 and Z3 20 are the same or different and selected among OH, OR' and OR 4 can be obtained by Nsubstitution of a compound of the formula R2 Z1 CONHCH2 z 3 Z2 --I N H wherein R 2, Z1, Z2 and Z3 have the definition given above, with a compound of the formula 30 R 3 -CH2 -X2 wherein R' has the definition given in A and X2 is a leaving group, such as chlorine, bromine, sulphate, phosphate, bensenesulphonate or toluenesulphonate.

The reaction can be effected by treating the reactants at 0-1 00C in a suitable solvent, e.g.

acetone, alcohols, dimethy1formamide (DIVIF), dimethylsulphoxide (DIVISO) in the presence of a base, for example NaOH or K2CO3.

C. The compounds of the formula I with the definition as in A with the exception that one of Z1, Z2 and Z3 is NH2 and the others OH, OR', OR 4 or SRI, can be obtained by reduction of a 40 compound of the formula R 2 z 1 CONHCH 1-7 2 _\ N z 2 CH R3 1 2 wherein R2 and R 3 have the definition given in A and one of Z, Z2 and Z3 is N02 and the others are OH, OW, OR' or SR 4.

The reduction can be performed by catalytic hydrogenation (R 2: halogen) or by treatment with FeS04 X 7H20 in ammonia.

D. The compounds of the formula 1 wherein Z', Z2 or Z3 is the same or different and selected among OH and OR 4, NH2, NR 4, NHR 4, SH and SR 4 and R 2 and R 3 are as defined in A can be obtained by reduction of a compound of the formula R 2 z 1 CONHCH 2 N" z 3 z 2 COR 3 wherein R 2, R 3, Z1, Z2 and Z3 have the definitions given above.

Suitable reducing agents working on the less sterically hindered amide group are a) LiAIH, and alkoxy complexes thereof; b) NaBH4 with addition of transition metal salts, or AIC13 or BF3 or65 6 GB 2153 354A 6 POC13 or carboxylic acids such as CH3COOH and CFCOOH; c) BA.

The reaction is preferably effected in alkyl ethers, such as diethlether, dimethoxyethane, diglyme, THF, dioxane, at temperatures from O'C to reflux temperatures of the reaction mixtures.

E. The compounds of the formula I with the definition as in A with the exception that one or 5 two Of Z1, Z2 and Z3 is a hydroxy group, can be obtained by deprotection of a compound of the formula R Z CONHCH 2 \N Z3 Z2 1 -R3 1 wherein R 2, R 3, Z1, Z2 and Z3 have the above definition with the exception that Z1, Z2 and Z3 are 15 suitably protected phenol groups corresponding to the hydroxy groups in the product.

Suitable standard phenol protective groups can be groups such as trimethylsilyl, t-butyldimethylsilyl, tetra hyd ropyra nyl, benzyl, methoxyethoxymethyl, methoxymethyl, methylthiomethyl, aliphatic or aromatic esters, carbonates or cyclic acetals, ketals or esters when Z2 = Z 3 = OH in the product. The protective groups can be removed by standard procedures (T.W. Greene, in 20 "Protective Groups in Organic Synthesis", Wiley, New York, 1981, p. 87- 113).

A special form of protective group is represented by Z' or Z2 being alkoxy.

Thus, the compounds of the formula I with the definition as in A, with the exception that Z' or Z2 is hydroxy and the remaining Zi being OH, OR', HN, NRI, NHR", or SR 4, can be obtained by 2 dealkylation of a compound of the formula R 2 z 1 CONHCH 2 -\ N Z 3 Z 2 CH 2_ R 3 wherein R 2, R 3, Z1, Z2 and Z3 have the above definition with the exception that Z' or Z2 being OR', resulting in the corresponding hydroxy compound in the reaction.

Suitable reagents are Br6nsted acids (HBr, HI), Lewis acids (AIC13, AlBr3, A113, BBr3, BCl,, 9- 35 bromo-9-borabicyclo[3.3.0]nonane, NaBHJ12), nucleophilic reagents (sodium ethanethiolate, sodium phenylmethaneselenolate) and others (iodotrimethylsilane).

The reaction with Br6nsted acids is performed at elevated temperatures preferably with a co solvent like acetic acid or in the presence of a phase-transfer catalyst. The reaction with Lewis acids can be performed in refluxing benzene or carbon disulfide (aluminium halides) and 40 halogenated solvents like dichloromethane at - 75'C to 25C (boron halides). Elevated temperature in dimethy1formamide is suitable for nucleophilic reagents.

F. The compounds of the formula I with the definition as in A with the exception that R 2 is Br or Cl can be obtained by reaction of a compound of the formula Z1 CONHCH 2 N Z 3 Z 2 1 CH 2 _R3 wherein R 3, Z1, Z2 and Z3 have the above given definition with a halogenating reagent such as halogen, a sulphurylhalogenide (preferably sulphurylchloride) or a halogen-dioxane complex.

Chlorination is effected by treating the starting compound witn chlorine with or without Lewis acid catalysis or with sulphurylchloride, HOD, N-chloroamides in the presence of acid catalyst in 55 suitable solvent, e.g. chloroform, nitrobenzene.

Bromination is carried out with Br, with or without Lewis acid catalysis or bromination in acetic acid in the presence of a base e.g. sodium acetate or by using bromine-dioxane complex. Other reagents can be using among them HOBr and N-bromoamides especially N-bromosuccin- imide with acid catalysis.

G. The compounds of the formula I with the definition as in A with the exception that Z' and/or Z2 is OR', NRI or SRI can be obtained by reaction of a compound of the formula 2 7 GB 2 153 354A 7 halogenZ2 R2 Z1 CONHCH2 N CH 3 2 -R wherein R 2, Z1, Z2 and R3 have the above given definition and halogen is e.g. Cl, Br or 1, with potassium hydroxide or sodium hydroxide in aqueous media, such as water in DMSO.

The reaction may be performed in water at 1 OWC in the presence of copper bronze or copper 10 sulphate.

H. The compounds of the formula 1 with the definition as in A with the exception that R 2 is a hydrogen atom can be obtained by catalytic hydrogenation of a compound of the formula halogen Z1 CONHCH 27E N 1 3 3RZ2 CH 2 R wherein R 3, Z1, Z2 and Z3 have the above given definition, and halogen is e.g. Cl, Br or 1.

The reaction is effected in a suitable solvent, e.g. methanol, ethanol.

1. The compounds of the formula I with the definition than at least one Zi is OR, and the remaining Zi are (is) OR', NR 4 or SR 4 and the definition of R 2 3 2 and R as in A, can be obtained by 5 reaction of a compound of the formula R 2 Z 1 CONHCH 2 -1 3 3 Z2 CH 2 R wherein R 2 and R3 have the above definition and Zi is defined as above with the exception that the Zi which is/are OR' in the end product is OH in the starting material, with a compound of 35 the formula R 1_X3 wherein R' has the above definition and X3 is a suitable leaving group such as halogen (Cl, Br), acyloxy, azide or azolide without solvent or in a suitable solvent such as benzene or chloroform 40 possibly with acid catalyst (e.g. CF,COOH, H2S04) or by using a tertiary amine as solvent and/or catalyst.

In the case of R' being monoalkylcarbamoyl the reaction can also be performed with an isocyanate.

Intermediates The compounds of the formula R2Z 1 COOH 3 Z2 11 wherein Zi, being Z1, Z2 or Z3, is the same or different and selected among OH, OR', NI-12, NR 4 4 2, NHR SH, SR 4 and OR 4 wherein R' is a formyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkylcarbamoyl group and R 4 is a lower alkyl group, R 2 is a hydrogen, a halogen, a lower alkyl or a lower trifluoroalkyl group, provided that at least one of Z', Z2 and Z3 is a group OR 4 and further provided that when Z2 is OH or NI-12, Z' is 60 NR 4 4 4 2, NHR21 SH, SR or OR are valuable intermediates for the preparation of the compounds of this invention by the process A.

The compounds of the formula 8 GB 2153 354A 8 R2 0A1 COOH 5 A3_Z' 2 wherein A3 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom, a halogen atom, a lower alkyl group or a lower trifluoroalkyl group, 10 Z is a moiety selected among oxygen, sulphur, nitrogen and alkylsubstituted nitrogen.

A' is a hydrogen atom, a lower alkyl group, a formyl group, an acyl group, an alkoxycarbonyl group or a mono- or di-alkylcarbamoyl group, A 2 is a methyl or an ethyl group, are a subgroup within the group of compounds of the formula 11.

Compounds of the formula 1 wherein one, two or three of V, Z2 and Z3 is a suitably protected phenol group are valuable intermediates for the preparation of deprotected compounds of the invention according to the process E.

The compounds of the formula R2 OA 1 1 CONNCH2- A3_Z 2 CH 2R wherein A3 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom, a halogen atom, a lower alkyl group or a lower trifluoroalkyl group, 30 Z is a moiety selected among oxygen, sulphur, nitrogen and aikyl- substituted nitrogen, A is a lower alkyl group, A2 is a methyl or an ethyl group, R3 is a hydrogen atom, a lower alkyl group, an alkenyl group, an alkynyl group or a phenyl group, which phenyl group could optionally be substituted by one or more of fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy or ethoxy in the ortho, meta or para positions, or 35 optionally substituted by methylenedioxy, are a subgroup within the group of compounds of the formula 1, useful as intermediates for the preparation of dealkylated compounds of this invention. The intermediates are prepared by the method described in A. 40 Intermediates of the formula R2 Z1 /LY-COOH 45 2 3 z wherein R 2, Z1, Z2 and Z' are as defined above, may be prepared by i) treating a compound of the formula R2 z 1 COOH Z3 z 2 wherein R 2 is as defined above and Z', Z2 and Z3 are OR 4, wherein R 4 is as defined above, with a Lewis acid such as boron tribromide, boron trichloride or aluminum chloride or hydrobromic acid, ii) treating a compound of the formula 9 GB 2 153 354A 9 R 2 Z 1 w 1 Z 3 Z 2 wherein R 2 is as defined previously with the exception of Br and 1; Z1 Z2 and Z3 being alkoxy, dialkylamino or alkylthio; alternatively Z1, Z2 and Z3 can be a suitably protected derivative like methoxymethyl ether, tetra hyd ropyranyl ether, t-butoxycarbonylamine or t-butylcarbonyiamin 10 which is deprotected after the reaction, with alkyl- or aryllithium followed by reaction with carbon dioxide and acidification. iii) treating a compound of the formula Z 1 C COOH Z3 Z2 wherein Z1, Z2 and Z3 are as defined previously, with halogen, a sulfurylhalogenide (preferably S02C12) or a halogen-dioxane complex gives compounds with R 2 being halogen.

Working Examples Example 1. (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyll-3-bromo-2,5,6trimethoxybenzamide Method 25 A.

A solution of 3-bromo-2,5,6-trimethoxybenzoic acid (4.5 g, 0.015 mol) in 60 mi toluene was treated with thionyl chloride (4.5 g, 0.038 mol) at 6WC for 1 h. The solvent was evaporated and the residue dissolved in 20 mi CI-IC13. A solution of (S)-(-)-2- aminomethyf-l -ethyl pyrrolidine in 40 mi CI-IC13 was added. The temperature rose to 45'C. After 0.5h the solvent was removed 30 and the residue was neutralized with 100 mi 1 -M NaOH. Extraction with 3 X 100 mi ether, drying and evaporation gave 5.8 g of title compound. Crystallization from diisopropylether gave 4.8 9 (79%). M.p. 106-107'C. NMR: One aromatic singlet at 7.07 ppm and three methoxy singlets at 3.86, 3.85 and 3.84 ppm. Carbon-1 3 signals at 164.6(7), 149. 9(5), 147.6(2), 145.9(6), 128.6(1), 117.0(4) and 111. 1 (3) ppm, respectively.

Anal. (C,H2,BM204) %C: calcd 50.88, found 50,84; %H: calcd 6.28, found 6. 27; %N: calcd 6.98, found 6.96.

Example 2. (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-chloro-2,5,6trimethoxybenzamid e Method A. 3-chforo-2,5,6-trimethoxybenzoic acid 2,5,6-trimethoxybenzoic acid 5.0 g (0.024 mol) was suspended in 75 mi of CHCI, and cooled to WC. 1.9 mi (0.024 M01) Of S02C12 was added under N2atm. The reaction was stirred for 2h and allowed to slowly attain room temperature. The reaction mixture was diluted 100 mi CHCI, and washed with 200 mi H20. The aqueous layer was washed with 50 mi CHCI, and the combined organic layer was dried (Na2SO4) and the solvent was evaporated. Gave 5.5 g (95%) of 3-chloro-2,5,6-trimethoxybenzoic acid (oil). Mw: 246.7.

(S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyll-3-chforo-2,5,6trimethoxybenzamid e A solution of 3-chloro-2,5,6-trimethoxybenzoic acid 5.5 9 (0.023 mol), DIVIF and SOCI, in 50 toluene was stirred at 5WC under N2-atm. until gas evolution stops. The solvent was evaporated and the residue was dissolved in 100 mi CHCI, and evaporated again. The residue was dissolved in 75 mi CHCI, and mixtured with a solution of (S)-(-)-2aminoethyi-l-ethylpyrrolidine in 10 mi CI-ICI, The mixture was stirred at room temperature for 3 hours and then extracted with 2 X 100 m] 1 M HCL The combined aqueous layer was alkalified with 45% NaOH (aq) and then extracted with 2 X 150 mi CH2C12. The combined organic layer was dried (Na,SOJ and the solvent was evaporated. Gave 4.8 g (60%) crystallizing residue. Recrystallization from 50 m) iPr20 gave 2.1 g of title compound, m.p. 11 8-120'C (26%).

Example 3. (S)-(-)-N-[(1-ethyl-2-pyrrolidinyi)methyll-2,3,6trimethoxybenzamide Method A.

2,3,6-Trimethoxybenzoic acid (4.2 g, 0.020 mol) was treated with thionyl chloride (7.1 g, 0.060 mol) in toluene (150 mi) at 65'C for 1 h. The solvent was removed in vacuo and the residue was dissolved in 50 mi chloroform. A solution of (S)+)- Wethyl-2- a m i no methyl pyrro lid i ne (3.8 g, 0.030 mol) in 50 mi chloroform was added and stirred at 40C for 30 min. Addition of sodium hydroxide (20 mi, 2-N), separation and evaporationof the organic layer gave 4.5 9 of 65 GB 2 153 354A 10 title compound Features of the nuclear magnetic resonance spectrum are given below. 'H NMR (CDC13) Sppm, 6.87 (d, 1 H), 6.58 (d, 1 H, J = 9.1 Hz), 3.88 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H). 13C NMR (CDC13) SPPM, 165. 6, 150.2, 147.0, 146.9, 114.3, 113.4, 106.5.

Example 4. (S)-(-)-N-[(1-ethyl-2-pyrrolidinyi)methyll-3-ethyl-2,5,6trimethoxybenzamide Method A.

3-Ethy]-2,5,6-trimethoxybenzoic acid (2.0 g, 0.0083 mol) was treated with thionyl chloride (1.2 g, 0.010 mol) in 20 mi toluene, containing 3 drops of dimethylformamide as a catalyst, at 10 5WC for 1.5h. The solvent was removed. The residue, consisting of crude 3-ethyl-2,5,6trimethoxybenzoyl chloride, was dissolved in 20 m[ chloroform and mixed with a solution of (S)(-)- 1 -ethyl-2-a m ino methyl pyrrol id i ne (1.3 g, 0.010 mol) in 20 mi chloroform. After 16h the reaction mixture was extracted with 2 X 50 mi 1-N HCL The aqueous layer was made alkaline with 30% NaOH. Extraction with 2 X 75 m[ chloroform, drying (Na2SOJ and evaporation of the solvent gave 2.0 g. Yield 71 %. M.p. 85-87'C from diisopropylether. []20 = - 71 (c = 0.74, 15 a D acetone). 13 C-NIVIR (CDC1,) 6 166.0 (CONH), 149.1 (C-2), 148.2 (C-6), 144.3 (C-5), 133.0 (C3), 127.2 (CA), 113.8 (C4) (aromatic signals only) ppm.

Example 5. (S)-(-)-N-[(1-Ethyl-2-pyrrolidinyl)methyll-3-propyl-2,5,6trimethoxybenzamid e (Method 20 A) 3-Propyi-2,5,6-trimethoxybenzoic acid (23 g, 0.09 mol) was treated with thionyl chloride and (2S)-(-)-1-ethyi-2-aminomethylpyrrolidine as described in example 4. Yield 10.6 g (32%). M.p.

68-70'C (i-Pr20). 'H-NMR (CDC'3): 8 6.73 (s, 1 H), 6.40 (b, 1 H), 3.85 (sx2, 6H), 3.76 (s, 3H), 0.9-3.8 (m, 21 H) ppm.

Example 6. (R)-(+)-N-[(1-Benzyl-2-pyrrolidinyl)methyl]-3-br.omo-2,5,6trimethoxybenzami de (Method A) 3-Bromo-2,5,6-trimethoxybenzoyl chloride (8 mmol) was reacted with (2R)-1-benzyi-2-aminomethylpyrrolidine (6.5 mmol) in 15 mi dichforomethane in analogy with example 1. Purification 30 by flash chromatography on Si02 with i-Pr,O/MeOH/NH3 100:10:1 as eluent gave 1. 17 g (39%). M.p. 11 2-114'C. [a122 = + 57' (c = 0.52, acetone). 'H-NMR (CDC1,): Three methoxy D singlets at 3.85, 3.84 and 3.83 ppm. UC-NIVIR (CDC'3): 8 164.7 (CONH), 149.9, 147.7, 146.1, 139.3, 128.9, 128.7, 128,3, 127.0, 117.3, 111.1 (aromatic) ppm. Mass spectrum (El, 70 eV): m/z 464/462 (M, 0.14%/0.11%), 160 (100%), 91 (52%).

Example 7. (S)-(-)-N-[(1-Ethyl-2-pyrrolidinyl)methyl]-2-amino-3-bromo-5,6dimethoxybenz amide (Method A) To a solution of 2-amino-3-bromo-5,6-dimethoxybenzoic acid (0.96 9, 3 mmol) and triethy lamine (0.58 m[, 4.2 mmol) in 15 mi tetrahyd rofu ran /dich loromethane (1:1) was added ethyl chloroformate (0.32 mi, 3.4 mmol) at - 2WC. After stirring for 45 min. at - 2WC a solution 40 of (2S)-(+1 -ethyl-2-aminomethylpyrrolidine in 10 mi dichloromethane was added at 2WC.

After stirring for 3 h at room temperature the mixture was washed with water and extracted with 0.5 M HCL The aqueous phase was made alkaline and extracted twice with dichloromethane.

Drying (Na2S04) and evaporation gave 0.45 g crude material which was purified by chromato graphy on a C, reversed phase column with H,,0/MeOH/NH3 40:60:0.3 as eluent to give 45 0.25 g (22%) pure product as an oil.

Anal. (C,,H2,BrN,03): Caled: C, 49.75; H, 6.26; N, 10.88. Found: C, 49,90; H, 6.31; N, 10.69.

H-NMR (CDC1,): 81.11 (t, CH,), 1.7-3.9 (multiplets, 11 H), 3.80 and 3.82 (two s, (OMeM, 5.80 (b, N11,), 7.14 (s, 4-H), 7.9 (b, NH) ppm. '3C-NMR (CDC1,): 8 167.0 (CONH), 148.1, 50 143.7, 140.9, 120.3, 113.0, 104.9 (aromatic) ppm.

Example 8. (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyll-3-bromo-5-hydroxy-2, 6-dimethoxybe nzamide Method A.

3,5-Dibromo-2,6-dimethoxybenzoic acid (10.0 9, 0.036 mol) was dissolved in 200 mi 10% 55 sodium hydroxide. 1.0 g of copper bronze powder was added and the mixture was heated at 1 OWC for 6 h. After cooling the mixture was neutralized with concentrated hydrochloric acid and extracted with 2 X 200 m] methylene chloride. Drying and evaporation of the solvent gave 3.5 g of brown resine consisting of 3-bromo-5-hydroxy-2,6- dimethoxybenzoic acid.

The residue was treated with thionyl chloride (3.5 g, 0.03 mol) in 50 mi toluene at 65,C for 60 1 h. The solvent was removed in vacuo and the residue was dissolved in 30 mi chloroform. A solution of (S)-(-)-1-ethyi-2-aminomethylpyrrolidine in 15 mi chloroform was added and the mixture was stirred for 1 h at 3WC. Water and 20 mi 2-N NaOH was added. The product was extracted with chloroform and subjected to column chromatography (Si-gel, Merck Lichrosorb in CH2C12-C^01-1-NH, 90:9A). Gave 0.35 g of title compound as an oil.

11 GB 2 153 354A 11 Mass spectrum: Molecular peak 386/388 corresponding to C16H23BrN204, NMR: (C13C13) proton. 8 ppm 7.56 (b, 5-01-1), 7.03 (s, H4), 6.83 (b, NH), 3.80 (s, CH,O), 3.77 (s, CH30), 1.7-3.8 (m, 11 H), 1. 11 (t, CH3)' Carbon-1 3: 8 ppm 165.4 CONH, 147.2 C,OH, 146.6 C2-OMe, 144.4 C,-OMe, 127.0 C,-CONI-1, 121.2 C4-H, 111.3 C3-Br.

Example 9. (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyll-3-bromo-2-hydroxy5, 6-dimethoxyben zamide and (S)-(-)-3-Bromo-N-[(1-ethyl-2pyrrolidinyl)methyll-6-hydroxy-2,5-dimethoxybe nzamide Method E.

a) Compound (S)-(-)-N-[(1-ethyi-2-pyrrolidinyi)methyi]-3-bromo-2,5,6trimethoxybenzamide (8.1 g, 0.020 mol) was dissolved in 100 mi CH2C12. 3-M HCI-ether (7.3 mi, 0.022 mol) was 10 added at room temperature followed by a solution of boron tribromide (5.5 g, 0.022 mol) in 40 mi CH2C12. After 1 h at 2WC 2-M ammonia (50 mi) was added, and the organic layer was separated, dried and evaporated. The residue (6.1 g) shows two peaks in GC with retention times 8.5 and 6.8 min, respectively, and two spots on TLC (silica in methanol- diisopropylether, 1:4) in the ratio 2A. The major product was isolated by column chromatography to give 3.0 g 15 of first title product. The hydrochloric was crystallized from 15 m] acetone-ether. M.p.

135-1 37'C.

Anal. (CH24BrCIN204): %C: calcd 45.35, found 45.22; %H: calcd 5.71, found 5.67; %N:

calcd 6.61, found 6.56.; %Br: calcd 18.86, found 18.75; %Cl: calcd 8.37, found 8.47.

1 H-NMR: (CDC13, 8 ppm) 7.28 (s, 1 H), 3.93 (s, 3H), 3.84 (s, 3H), 3.70 (dd, 1 H), 3.30 (m, 20 2H), 2.84 (dq, 1 H), 2.6 (m, 1 H), 2.20 (m, 2H), 1.4-1.8 (m, 4H), 1. 13 (t, 3H).

13H-NMR: aromatic region 169.2, 153.5, 147.9, 144.6, 121.9, 109.0, 105.5.

From the collected fractions above which contained the minor compound 0. 92 g of second title product was obtained. M.p. 97-99'C from hexane-ethanol (20:1).

WNMR (CDC1,): 88.9 (b, NH), 7.06 (s, H-4), 3.86 (s, OCHJ, 3.84 (s, OCH3), 1.6-3.9 (m, 25 12 H), 1. 13 (t, CHJ ppm.

13C-NIVIR (CDC13): 8 169.1 (CONH), 153.4 (C-2), 148.8 (C-6), 146.7 (C-5), 118.2 (C4), 108.9 (CA), 103.8 (C-3) (aromatic) ppm.

= laID - 53' (c = 1,52, acetone).

b) From an anhydrous stock solution of (S)-N-[(1-ethyi-2pyrrolidinyi)methyll-3-bromo-5,6- 30 dimethoxy-2-trimethyisiloxybenzamide was withdrawn 0.5 mmol and treated with water at room temperature which caused rapid formation of the first title compound which had identical NMR and GC retention time as the compound described in a).

Example 10.(S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyll-3-chloro-2-hydroxy5,6-dimetho xybenzam- 35 ide and (S)-(-)-3-Chloro-N-[(1-ethyl-2-pyrrolidinyl)methyi]-6-hydroxy -2, 5-dimethoxybenzamide Method E.

To a solution of 2.0 g (S)+)- N -[(1 -ethy 1-2-pyrro lid i nyi) methyll3-ch lo ro-2, 5,6-tri methoxyben zamide (0.0056 mol) and 1.9 mi 3M HCI-ether (0.0056 mol) in 20 mi CHP2, was a solution of 1.4 g BBr, in 10 mi CH2C12 added, over a period of 1 hour. After 1 hour at room temperature 40 was the reaction mixture extracted with concentrated ammonia. The alkalified aqueous layer was extracted with 2 X 100 mi CH2C12. The organic layer was dried (Na2S04) and evaporated. Gave a residue 1.3 9. TLC (silica in iPr20:MeOH:NH, 89:10: 1) showed two spots Rf 0.45 and Rf 0.30, respectively. 0.9 9 of the mixture was separated by column chromatography and gave 0.4 9 of the first title compound. The mesylate was crystallized from acetone. M.p. 165-1 66'C. 45 Anal. (Cl,H23CIN204): %C: calcd 46.52, found 46.53; %H: calcd 6.20, found 6.14; %C]: calcd 8.08, found 7.89; %N: calcd 6.38, found 6.30; %0: calcd 25.52, found 25. 39; %S: calcd 7.31, found 7.38.

From the selected fractions above, which contained the minor compound, was prepared 0. 10 9 of the second title compound as an oil. [a]20 = - 62 (c = 0. 18, acetone).

1) H-NMR (CDC1,): 8 8.9 (b, NH), 6.92 (s, H-4), 3.86 (s, OCHJJ, 1.6-3.8 (m, 11 H), 1. 13 (t, CHJ ppm.

13 C-NMR (C13C13): 8 169.4 (CONH), 153.1 (C-6), 148.0 (C-2), 146.6 (C-5), 115.9 (C4), 115.7 (C-3), 108.8 (CA) (aromatic) ppm.

Example 11. (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyll-3-ethyl-2-hydroxy5,6-dimethoxybe nzamide and (S)(-)-N-[(1-Ethyl-2-pyrrolidinyl)methyl]-3-ethyl-6-hydroxy-2,5dimethoxybe nzamide Method E.

A solution of (S)+)-N -[(1 -ethyl-2-pyrro 1 i d i nyi) m ethyl]- 3-ethyl2,5,6-tri methoxybenza m i d e (0.80 g, 0.002 mol) in 25 mi CH2C12 was treated with 3-N HCI-ether (1 mi, 0.003 mol) followed by 60 the addition of a solution of boron tribromide (0.6 g, 0.0023 mol) in 10 mi CH2C12 at ambient temperature. Work up and chromatography in accordance with example 9 gave 0.4 g (54%) of the first title compound as an oil. Proton NMR: (CDC13 8 PPM: 9.2 (b, NH), 6.92 (s, H,), 3.90 (s, CH30), 3.84 (s, CH30), 1.7-3.8 (m, 13H), 1.17 (t, CH,), 1.13 (t, CH3). Carbon-1 3 NMR:

(C13C13) 8 PPM: 170.2 CONH, 154.7 C2-0H, 146.3 C,-OCH31 143.8 C,-OCH.3, 128.3 C3-C21-15, 65 12 GB 2 153 354A 12 119.0 CrH, 107.5 C,-CONH. GC: Retention time 6.6 min. at 260'C on 1 Om SE 54. The minor isomer has RT 7.8m.

The mesylate was prepared from ether by mixing one equivalent of methanesulfonic acid in acetone and recrystallizing from acetone. M.p. 153-1 55'C (acetone). Yield 0.32 g (38%).

Analysis (C,,H32N207S): %C: calcd 52.76, found 52.69; %H: calcd 7.46, found 7.33; %N:

calcd 6.48, found 6.44; %0: calcd 25.89, found 25.76; %S: calcd 7.41, found 7.27.

From the collected fractions above containing the minor isomer was prepared 0.3 g of the second title compound as the methanesulfonate. M.p. 137-1 38'C from acetone. [a]20 (ba D se) = - 48' (c = 1.0, acetone).

'H-NIVIR (CDC[,): 8 8.9 (b, NH), 6.79 (s, H-4), 3.87 (s, OCH,), 3.71 (s, OCH,), 1.6-3.9 10 13H), 1.23 (t, CHA 1.13 (t, CH.) ppm.

13 C-NIVIR (CDC'3): 8 170.2 (CONH), 151.9 (C-6), 149.8 (C-2), 146.1 (C-5), 125.5 (C-3), 115.8 (C-4), 108.0 (C-1) (aromatic) ppm.

Example 12.(S)-(-)-5,6-Dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyll-2hydroxy-3-prop yibenzam- 15 ide (Method E).

A solution of 10. 0 g (0. 02 7 mol) of (S)-(-)-N-[(1 -ethy]-2pyrrolidinyi)methyi]-3-propyi-2,5,6- trimethoxybenzamide was treated with 16 mi (0.027 mol) of 1.6M HCl-ether in 250 mi of methylene chloride. A solution of 6.8 g (0.027 mol) of boron tribromide in 50 mi methylene chloride was slowly added at 1 WC. The reaction mixture was stirred for 2 h at 2WC. 100 mi of 20 2M NH, was added. Extraction with 2 X 300 m] of CH2C12, drying (Na2SOJ and evaporation of the solvent gave 9.2 9 of two components in a 4:1 ratio. The residue was dissolved in 300 mi of ether and shaken with 2 X 50 mi of 1 N NaOH which exclusively removed the minor component from the ether layer. Drying and evaporation of the solvent gave 6.0 9 of the title compound as an oil. GC 5.5 min at 25WC (SE-54). Yield 63%.

13 C-NIVIR (CDCI,) 8 170.2 (CONH), 154.9 (C-2), 146.3 (C-6), 143.6 (C-5), 126.7 (C-3), 119.9 (C4), 107.5 (CA), 62.2 (OCH,), 62.1 (OCH,), 61.2 (C'-2), 57.2, 53.4, 47.7, 40.5, 32.0, 28.4, 22.6, 14.0, 13.9 (9 carbons) ppm.

The oil was dissolved in 75 mi acetone. A hot solution of 2.6 g of L( +)tartaric acid in 95 m[ 98% (aq) acetone was added which gave 4.5 g of the tartrate salt. M.p. 84- 85'C.

Example 13. (S)-(-)-2,5-Dimethoxy-N-[(1-ethyi-2-pyrrolidinyi)methyl]-6hydroxy-3-propyib enzam- ide Method E.

The combined alkaline aqueous layer of example 12 was washed with 50 mi ether and neutralized with ammonium chloride to pH 8.5. Extraction with 2 X 50 mi ether gave 1.3 g of 35 pure minor isomer as an oil.

GC (SE-54, 250'C) 6.0 min.

H-NMR (CDC13): 8 8.5 (b, NH), 6.77 (s, H-4), 3.86 (s, OCH3), 3.71 (s, OCH, ), 1.6-3.9 (m, H), 1. 13 (t, 3 H), 0. 98 (t, 3 H) ppm.

"C-NMR (CDCI,): 8 170.1 (CONH), 151.8 (C-6), 149.9 (C-2), 145.8 (C-5), 123.9 (C-3), 115.840 (C4), 107.9 (CA) (aromatic) ppm.

Example 14. (S)-(-)-N-[1-Allyl-2-pyrrolidinyl)methyll-3-bromo-2-hydroxy-5, 6-dimethoxyben zamide and (S)-(-)-N-[(1-Allyl-2-pyrrolidinyl)methyll-3bromo-6-hydroxy-2,5-dimethoxybe nzamide (Method E) By the same method as described in example 9, (S)-(-)-N[(1-Aliyi-2pyrrolidinyi)methyi]-3bromo-2,5,6-trimethoxybenzamide prepared in example 21 was transformed into the first title compound. Yield 48% of colourless oil. [aD - 62' (c = 1.8, acetone). 'H-N M R (CDCI,): 89. 05 (b, N H), 7.2 7 (s, H-4), 5.91 (m, vinyl-H), 5.19 (dd, 1 H), 5.12 (d, 1 H), 3.92 (s, OCH,), 3.83 (s. OCHJ, 1.6-3.8 (m, 11 H) ppm. 13 C-NMR (CDCI,): 8 169.3 (CONH), 153.6 (C-2), 148.0 (C-6), 144.6 (C-5), 135.9 (CH-4), 122.0 (vinyl-CH), 117.0 (vinyl-CH,), 109. 1 (CA), 105.6 (C-3), 61.5 (CH-2% 61.4 (OCH3-5), 57.2 (OCH3-6), 56.9 (NHCH,), 54.2 (NCH,), 40.6 (CH,-5% 28.4 (CH, -3% 22.8 (CH24') ppm.

From the fractions containing the minor component was isolated 0.06 9 of the second title compound as an oil. [a]20 = - 51 ' (c = 0. 18, acetone). D 'H-WR (CDCI,): 8 8.9 (b, NH), 7.07 (s, H-4), 5.90 (m, 1 H), 5.20 (dd, 1 H, J = 22 Hz, 1.5 Hz), 5.16 (d, 1 H, J = 16 Hz), 3.87 (s, OCH,), 3.84 (s, OCH,), 1.6-3.8 (m, 11 H) ppm.

Example 15. (R)-(+)-N-[(1-Benzy]-2-pyrrolidinyl)methyl]-3-bromo-2-hydroxy5,6-dimethoxyb en- zamide and (R)-(+)-N-[(1-Benzy]-2-pyrrolidinyl)methyll-3-bromo-6-hydroxy2,5-dimethoxyb en- 60 zamide (Method E).

(R)-( +)-N-[(1 -Benzyi-2-pyrrolidinyi)methyi]-3-bromo-2,5,6trimethoxybenzamide (950 mg, 2.05 mmol) was dissolved in 30 mi dichloromethane and cooled with ice. Solutions of 4M HCI in ether (0.5 mi, 2 mmol) followed by 3.2 mi 0.65 M boron tribromide in dichloromethane (2.1 mmol) were added. After stirring for 1 h 30 mi 0.7 M NH, were added, the mixture extracted 65 13 GB 2 153 354A 13 with dichloromethane. The solvent was evaporated, the residue dissolved in Et20, washed with brine, dried (M9S04) and evaporated to give 923 mg (100%) of two isomeric phenols. GC (SE 30, capillary column, 27WC): retention times 10. 1. min and 12.4 min (ratio 3:7). The phenols were separated by flash chromatography on SiO, with Et20/MeOH/NH3 100:3:0.3 to give 495 5 mg (54%) of the first title compound as an oil. [a]22 = + 94 (c = 0.52, acetone). 'H-NMR (CDC]3): 8 7.25 (s, overlapping with Ph, 4-H), 3.81 D and 3.75 (two s, (OMe)2). Mass spectrum (E], 70 ev): m/z 449/447 (M-H, 0.57/0.61 %), 261/259 (ArCO, 1.3/1.3%), 160 (100%), 91 (51%).

From the fractions containing the minor component was isolated 229 mg (25%) of the second 10 title compound as an oil.

22 = MD + 81' (c = 1.1, acetone). 'H-NMR (CDC13): 87.12 (s, 4-H), 3.79 and 3.84 (two s, (0 Me)2). Mass spectrum (El, 70 eV): m/z 449/447 (M-H, 0. 31/0.33%), 261/259 (ArCO, 0.86/0.91%), 160 (100%), 91 (54%).

Example 16. (S)-(-)-N-[(1-Ethyl-2pyrrolidinyl)methyl]-5,6-dimethoxy-2hydroxybenzamide hydro chloride (Method H) A solution of S(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-5, 6-dimethoxybenza m- ide HCI (0.20 9, 0.47 mmol) in 10 mi of 95% ethanol was hydrogenated for 2.5h at ambient pressure and temperature with 10 mg of palladium on charcoal as the catalyst. Filtration and 20 evaporation of the solvent gave 0. 18 g of the title products as an oil. Its chromatographic and spectroscopic properties (TLC, GC, NIVIR) were identical of those of the minor product obtained from the boron tribromide demethylation of (S)-(-)-N-[(1-ethyi-2- pyrrolidinyi)methyi]-2,5,6-trimethoxybenzamide.

Gas chromatography (GC): Retention time at 23WC on 25m SE-52 in 2.50 min (72% of that 25 of its isomer).

NMR: proton (CDC'3) 8 ppm 8.4 (b, NH), 7.02 (d, J = 9. 15 Hz, H,,), 6.70 (d, H3), 3.93 (s, CH30), 3.83 (s, CH,O), 1.7-3.8 (m, 11 H), 1.13 (t, CH,CH2), NMR: carbon-1 3 (CDC'3) 8 PPM: 169.8 CONH, 156.9 C2-0H, 148.3 C,-OMe, 144. 4 C,-OMe, 118-9 C4-H, 113.1 C3-11, 108.3 C,-CONI-1.

Example 17. (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-hydroxy-2,6dimethoxybenzamide (Method G) S(+3-Bromo-W[(1 -ethyl-2-pyrrolidinyi)methyi]-2,6-dimethoxybenzamide X HCI X H20 (1 0 91 0.0026 mol) was dissolved in 25 mI dimethyisulphoxide. A suspension of crushed potassium 35 hydroxide (1.0 g, 0.018 mol) in 5 mI water was added and the mixture was heated at reflux for 2h. After cooling 200 m] of water was added and the reaction mixture was neutralized and extracted with chloroform. Drying and evaporation of the solvent gave a residue containing a mixture of several products including the starting material. Separation on silica column with CH2C'2-C2H,OH-NH3 (90:9A) gave 0.05 g of the title compound as an oil.

NMR: (CDC'3) 8 PPM 9.0 (b, NH), 6.88 (d, J = 9.15 Hz, H4), 6.29 (d, H,), 3.95 (s, CH30), 3.93 (s, CH30), 1.7-3.8 (m, 11 H), 1. 14 (t, CH3) The chromatographic and spectroscopic properties (TLC, GC, NMR, MS) were identical of those of the product obtained by catalytic hydrogenation of (S)-(-)-3- bromo-N-[(1-ethyi-2pyrrolidinyi)methyl]-5-hydroxy-2,6-dimethoxybenzamide.

Example 18. (S)-(-)-5-Amino-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]2hydroxy-6-metho xyben- zamide (Method Q Iron (11) sulphate heptahydrate (11 g, 0.04 mol) was dissolved in 25 mi water and added to a solution of (S)-(-)-3-bromo-N-[(1-ethyi-2-pyrrolidinyi)methyf]-2-hydroxy5-nitro-6-metho xybenzam- 50 ide (2.0 g, 0.005 mol) in 50 mi methanol. 30 mi concentrated ammonia (25%) was added and the mixture was stirred at WC for 1 h. Filtration and washing the precipitation with methanol water (1:1) was followed by neutralization with ammonium chloride to pH 8. Extraction with 4 X 75 m] ether, drying (Na2S04) and evaporation of the solvent gave 1.0 g of residue which crystallized upon standing. The dihydrochloride monohydrate was precipitated from HCl-ether and recrystallized from ethanol.

M.p. 102-105'C (dec.) Carbon-1 3 NMR: (CDC[3) ppm 169.2 CONH, 152.1 C2-0H, 145.2 C6-OCH, 132.1 C5-NI-121 124.5 C4-H, 109.2 C,-CONI-1, 107.3 C3-Br.

Analysis (Cl,H,,BrCl,N304): %C: calcd 38.90, found 39.04; %H: caicd 5.66, found 5.32; %Br: 60 calcd 17.25, found 17.17; %Cl: calcd 15.3 1, found 15. 18; %N: calcd 9.07, found 9.05.

Example 19. (S)-(-)-5-Amino-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyll-2, 6-dimethoxybenz amide (Method Q (S)-(-)-3-Bromo-N-[(1-ethyi-2-pyrrolidinyi)methyl]-5-nitro-2,6dimethoxybenz amide (2.1 g, 65 14 GB 2 153 354A 14 0.005 mol) was dissolved in a mixture of 50 mi methanol and 30 mi 14-N ammonia. A solution of iron (11) sulphate heptahydrate in 25 mi of water was added and the mixture was stirred at WC for 45 min. The inorganic salts were filtered off, washed with 50 mI aqueous methanol (50%), and the combined filtrate was extracted with 2 X 100 mi ether. The combined extract was neutralized with cone. HCI and shaken with 3 X 75 mi 1-N HCL The combined aqueous layer was treated with 30% NaOH to pH 10 and extracted with 3 X 100 mi ether. Drying and evaporation of the solvent gave 1.84 g of crude product as an oil. It was dissolved in 50 mI CH2C12 and 2 mI of 3-N HCI-ether was added. Evaporation of the solvent and dissolving the residue in 15 mi 2-propanol gave 1.8 g of the dihydrochloride monohydrate of the title 10 compound upon addition of 45 mi ethyl acetate. M.p. 11 OT (dec.). Yield 75%. NIVIR: 6.9 (s, H,), 6.5 (b, NH), 4.0 (b, NH2), 3.8 s (CH,0 + C1-1,0), 1.7-3.8 (m, 11 H), 1.1. (t, CH3). Analysis (C,,H2,BrCI2N, O,): %C: calcd 40.27, found 40.76; %H: calcd 5.91, found 5.86; %Br: calcd 16.74, found 16.22; %C[: calcd 14.86, found 14.01; %N: calcd 8.81, found 8.36.

Example 20. (S)-(-)-N-[(l-ethyl-2-pyrrolidinyl)methyl]-5-amino-2-hydroxy6-methoxybenzam ide (Method Q By the same method as described in Example 19 the following compound was prepared: (S)-(-)-N-[(l -ethyl-2-pyrrolidinyl)methyl]-5-amino-2-hydroxy-6- methoxybenzamide. 20 M.p. of the dihydrochloride: 102-105'C from ethanol.

Example 21. (S)-(-)-N-[(1-Allyl-2-pyrrolidinyl)methyl]-3-bromo-2,5,6trimethoxybenzamide (Method B) 3-Bromo-2,5,6-trimethoxybenzoyl chloride (1.48 9, 4.8 mmol) was reacted with (S)-(-)-1-trityi 2-aminomethylpyrrolidine (1. 51 g, 4.4 mmol) in 10 mi dichloromethane at room temperature 25 for 1 h. The solvent was evaporated and the residue was treated with 10 mI ethanol and 0. 1 mi cone. HCI during 1 h. After evaporation the residue was partitioned between 0.5M HCI and Et20. The aqueous phase was made alkaline, extracted with dichloromethane, dried (Na,S04) and evaporated to give 1.30 g (79%) (S)-3-bromo-N-(2-pyrrolidinyimethyi)- 2,5,6-trimethoxyben- zamide. An analytical sample of the hydrochloride was prepared. M.p. 181 - 1 82'C (EtOH/ace- 30 tone/Et,O).

To a mixture of (S)-(+)-3-bromo-N-(2-pyrrolidinyimethyi)-2,5,6trimethoxybenzamide (0.82 g, 0.0022 mol) and potassium carbonate (0.40 9, 0.003 mol) in 10 mi of dimethy[formamide, allylbromide (0.40 9, 0.0033 mol) in 4 mi DMF was added dropwise at 20'C. After 1 h 150 mi of water was added and the product was extracted with ether. The combined organic layer was shaken with 3 X 50 mI of 1 N HCI and the combined aqueous layer was made alkaline by addition of 20 mi of 1 ON NaOH. Extraction with methylene chloride (2 X 75 m]) gave 0.8 g of the desired benzamide. Crystallization from 12 mi of diisopropylether gave 0.33 9. M. p. 11 8-122'C. [a],"'= - 85 (c= 0.44, acetone).

'H-NMR (CDC'3): 8 7.07 (s, 1 H), 6.34 (b, 1 H), 5.85 (m, 1 H), 5.12 (dd, 2H), 3.86 (s, 3H), 3.84 (sx2, 6H), 3.76 (m, 1 H), 3.35 (m, 2H), 3.04 (m, 1 H), 2.88 (m, 1 H), 2.67 (b, 1 H), 2.22 (m, 1 H), 1.60-1.98 (m, 31-1) ppm. "IC-NIVIR (CDCI,): (5 164.6 (CONH), 149.9 (C-2), 147.6 (C5), 145.8 (C-6), 135.9 (C4, 128.6 (CA, 117.0 (allyl), 1 '16.9 (allyi), 111. 1 (C-3) ppm.

Example 22. (S)-(-)-N-[(1-Ethyl-2-pyrrolidinyi)methyll-3-bromc-2-hydroxy5,6-dimethoxybe nzam- 45 ide (Method F) (S)-N-[(1 -Ethyl-2-pyrroiidinyi)methyi]-2-hydroxy-5,6-dimethoxybenzamide (140 mg, 0.45 mmol) was dissolved in 5 mi dioxane. After addition of 0. 1 g K2CO, a solution of 30 td Br, in 2 mi dioxane was added. After stirring for 2 h the mixture was partitioned between 2 M NH3 and Et,O. Drying (NIgSOJ and evaporation of the organic layer gave 165 mg (95%) of the title compound having identical NIAR and GC retention time as the compound prepared in Example 9.

Example 23. (S)-N-[(1-Ethy]-2-pyrrolidinyl)methyll-3-bromo-2-hexadecanoyl5,6-dimethoxyb en- zamide (Method 1) To a solution of (S)- N -[(1 -ethyi2-pyrro lid i nyi)methyi]-3-bro mo-2- hyd roxy-5,6-d i m eth oxyben zamide mesylate (0.48 g, 1 mmol) in 10 m] of trifluoroacetic acid was added palmitoyl chloride (0.55 mi, 2 mmol). The reaction mixture was stirred at ambient temperature over molecular sieves for 20 h. After evaporation of the solvent in vacuo ether was added to the residue and filtered. The filtrate was washed several times with a saturated KI-ICO, solution and dried 60 (M9S04). After evaporation of the solvent in vacuo the resulting oil crystallized on cooling. Yield 0,42 9 (67%). M.p. 46-48'C. R, value is 0.21 for title compound and 0.32 for starting compound (S'02, TI-C-plates, 20% MeOH in i-Pr,0 as eluent).

Mass spectrum (El, 70eV) m/z 624/626 (M-).

GB 2 153 354A 15 Example 24. (S)-(-)-N-[(1-Ethyl-2-pyrrolidinyl)methyll-3,6-dibenzyloxy2methoxybenzamid e (Method A) A solution of 3,6-dibenzyioxy-2-methoxybenzoic acid (120 mg, 0. 33 mmol), thionyl chloride (120 mg, 1 mmol) and two drops of dimethylformamide as catalyst in 5 mi toluene was stirred at WC for 1.5 h. The solvent was evaporated and the residue dissolved in CH2C12 and evaporated again. This residue was dissolved in 8 mi CH2C12 and a solution of (S)-(-)-1-ethyl2aminomethylpyrrolidine (65 mg, 0.5 mmol) in 2 mi CH2C12 was added. After stirring overnight at room temperature the solvent was evaporated and the residue partitioned between 2 M HCl and ether. The aqueous phase was made alkaline, extracted with CH2C1, dried (Na2SOJ and evaporated to give a crude product. Purification by chromatography on S'02 with Wr20/hexane/MeOH/NH, 69:20:10:1 as eluent gave 145 mg (93%) pure title compound. M. p. 121-123'C. [a]22 = - 42' (c = 2.8, acetone).

D H NMR (CDC13) 8 7.39 and 7.38 (two s, CH2Ph), 6.89 and 6.59 (AB, 4-H and 5-H), 5.06 and 5.03 (two s, Ch2Ph), 3.95 (s, 0Me) ppm.

Mass spectrum (E], 70 eV): m/z 474 (M, 0. 13%), 347 (ArCO, 0.33%), 98 (100%), 91 (12%) 15 Example 25. (S)-(-)-[(1-Ethyl-2-pyrrolidinyl)methyl]-3,6-dihydroxy-2- methoxybenzamide (Method E) A mixture of (S)-(-)-[(1-ethyi-2-pyrrolidinyi)methyi]-3,6-dibenzyioxy-2methoxybenzamide (130 mg, 0.27 mmol), 5% Pd/C (50 mg), 0.5 mi 4 M HCl in ether and 5 mi ethanol was shaken in 20 a hydrogen atmosphere for 1 h. Filtration and evaporation of the solvent gave 90 mg pure title compound as an oily hydrochloride.

H NMR (CDC'3/CD3OD): 8 7.13 and 6.67 (AB, 4-H and 5-H), 3.99 (s, ON1e) ppm.

Mass spectrum (El, 70 eV): m/z 294 (M, 0.64%), 167 (ArCO, 1.4%), 98 (100%).

Example 26. (S)-(-)-[(1-Ethyl-2-pyrrolidinyl)methyll-3-bromo-2,5dihydroxy-6-methoxybenz amide (Method F) To a mixture of (S)-(-)-[(1-ethy]-2-pyrrolidinyi)methyi]-3,6-dihydroxy- 2methoxybenzamide hy drochloride (90 mg, 0.27 mmol), 0.5 mi dioxane and 0.1 mi acetic acid was added a solution of 18 tti bromine (0.35 mmol) in 0.5 mi dioxane. After stirring at room temperature for 1 h the 30 solvent was evaporated.

H NMR (CDCI,) showed complete removal of the aromatic AB system: 8 7.40 (s, 4-H), 4.05 (s, 0Me) ppm.

Mass spectrum (El, 70 eV): m/z 374/372 (M, 0.19%/0.18%), 247/245 (ArCO, 0.40%/0.40%),98(100%).

Example 27

By any of the methods described in the preceding examples the following compounds could be prepared:

(S)+)-N-[(1 -ethyi-2-pyrrolidinyi)methyll-2-hydroxy-5,6-dimethoxy-3methyibenzamide, (S)+)-N-[(1 -ethyl-2-pyrrol id i nyi) methyll- 5-bro m o2, 3-d i hyd roxy-6-meth oxybenza m i d e, (S)+)-N-[(1 -ethyi-2pyrrolidinyi)methyll-3-ethyi-2,5-dihydroxy-6-methoxybenzamide, (S)-(-)-N[(1 -ethyl-2-pyrrolidinyi)methyl]-5-amino-3-ethyi-2-hydroxy-6methoxybenzamide, (S)-(-)-N-[(1 -ethyi-2-pyrrolidinyl)methyi]-3-bromo-5,6diethoxy-2-hydroxybenzamide, Example 28

The following examples illustrate the preparation of pharmaceutical compositions of the invention. The wording -active substance- denotes a compound according to the present invention or a salt thereof.

Formulation A. Soft gelatin capsules 500 g of active substance were mixed with 500 g of corn oil, whereupon the mixture was filled in soft gelatin capsules, each capsule containing 100 mg of the mixture (i.e. 50 mg of active substance).

Formulation B. Soft gelatin capsules 500 9 of active substance were mixed with 750 9 of pea nut oil, whereupon the mixture was filled in soft gelatin capsules, each capsule containing 125 mg of the mixture (i.e. 50 mg of active substance).

Formulation C. Tablets kg of active substance were mixed with 20 kg of silicic acid of the trademark Aerosil. 45 kg of potato starch and 50 kg of lactose were mixed therewith and the mixture was moistened with a starch paste prepared from 5 kg of potato starch and distilled water, whereupon the mixture was granulated through a sieve. The granulate was dried and sieved, whereupon 2 kg 65 16 GB 2 153 354A 16 of magnesium stearate was mixed into it. Finally the mixture was pressed into tablets each weighing 172 mg.

Formulation D. Effervescing tablets 100 g of active substance, 140 9 of finely divided citric acid, 100 g of finely divided sodium 5 hydrogen carbonate, 3.5 9 of magnesium stearate and flavouring agents (q. s.) were mixed and the mixture was pressed into tablets each containing 100 mg of active substance.

Formulation E. Sustained release tablet 200 g of active substance were melted together with 50 g of stearic acid and 50 g of 10 carnauba wax. The mixture thus obtained was cooled and ground to a particle size of at most1 mm in diameter. The mixture thus obtained was mixed with 6 g of magnesium stearate and pressed into tablets each weighing 305 mg. Each tablet thus contains 200 mg of active substance.

Formulation F. Injection solution Active substance 3.000 mg Sodium pyrosulfite 0.500 mg Disodium edetate 0.100 mg 20 Sodium chloride 8.500 mg Sterile water for injection ad 1.00 mi Formulation G. Hard gelatine capsules g of active substance was mixed with 400 g of lactose and finally 2 g of magnesium 25 stearate was added. The mixture was then filled in hard gelatine capsules, each capsule containing 206 mg of the mixture (i.e. 5 mg of active substance).

Formulation H. Tablets 50 g of active substance was mixed with 1500 9 of lactose, 200 g of microcrystalline 30 cellulose and 10 g magnesium stearate. Tablets of 5 mg active substance with a core weight of 176 mg were finally comprotted.

Formulation 1. Depot preparation (S)-N-[(1 -ethyl-2-pyrrolidinyi) methyl]-3-bromo-2-hexadecanoyi 5,6-dimethoxybenzamide 200 mg Peanut oil ad 1 mi Pharmacology Introduction

A number of studies suggest that the antipsychotic action of neuroleptic drugs is in some way related to decrease in catecholamine transmission in the brain caused by these drugs and more specifically due to central dopamine (DA) receptor blockade in cortical and subcortical brain regions. Most compounds with an antipsychotic action effect several DA systems in the brain.

There is evidence that the antipsychotic action may be linked to blockade of DA receptors in the sub-cortical and cortical limbic structures (J. Pharm. Pharmacol. 25, 346, 1973; Lancet, 1027, 1976) while the wellknown extrapyramidal side effects produced by neuroleptic drugs are due to blockade of DA receptors in the nigroneostriatal DA system (intern. J. Neurol. 6, 27-45, 50 1967).

A. In vivo tests There are presently several techniques available to study DA receptor blockade in the brain in vivo. One method is based on the ability of antipyschotic drugs to block the behavioural effects induced by the DA agonist apornorphine in the rat. Several studies indicate an excellent correlation between the in vivo DA receptor blockade as measured in the apornorphine test and therapeutic efficacy of different antipsychotic drugs. Apomorphine produces in rats and other species a characteristic syndrome consisting of repetitive movements (stereotypies) and hyperac tivity which appear to be due to activation of postsynaptic DA receptors in the brain (J. Pharm. 60 Pharmacol. 19, 627, 1967; J. Neurol. Transm. 40, 97-113, 1977). The stereotypies (chewing, licking, biting) appear mainly to be induced via activation of DA receptors linked to the nigro neostriatal DA system (J. Psychiat. Res., 11, 1, 19 74) whereas the increased locomotion (hyperactivity) mainly appears to be due to activation of DA receptors in subcortical mesolimbic structures (nucleus olfactorium, nucleus accumbens) i.e. the mesolimbic DA system.

17 GB 2 153 354A 17 (J. Pharm. Pharmacol. 25, 1003, 1973).

A number of studies have demonstrated that neuroleptics of different structural classes block the apornorphine stereotypies in the rat and that this blockade is well related to blockade of DA transmission measured by biochemical or neurophysiological techniques. Thus, the antiapomorphine effect correlates well with changes in DA turnover produced by neuroleptic drugs (Eur. J. Pharmacol., 11, 303, 1970), DA receptor binding studies (Life Science, 17, 993-1002, 1976) and most important with antipsychotic efficacy (Nature, 263, 388-341, 1976).

Methods Male Sprague-Dawley rats (weighing 225-275 g) were used. The rats were observed in 10 perspex cages (40 (L) X 25 (w) X 30 (h) (cm) and the behaviour was scored 5, 20, 40 and 60 min. after apomorphine. The compounds were injected 60 min. prior to apomorphine hydrochloride (1 mg/kg) which was injected subcutaneously (s.c.) into the neck. This dose and form of administration was found to produce a very consistent response and very low variation in response strength. Further more, apomorphine given s.c. also produced a very consistent 15 hyperactivity.

Directly after injection, the animals were placed in the cages, one in each cage. Scoring of the stereotypies were performed by two separate methods. The first scoring system was a modified version of the system introduced by Costall and Naylor (1973). The strength of the stereotype was scored on a 0-3 scale as follows:

Score Description of stereotyped behaviour

2 0 No change in behaviour compared to saline controls 25 or sedated 1 Discontinuous sniffing Continous sniffing 3 Continous sniffing. Chewing, biting and licking.

In the second system the number of animals displaying hyperactivity caused by apomorphine were scored. Each group consisted of 6-8 animals. Saline controls were always run simultane ously. ED,,'s are in the first scoring system (0-3 scale), the doses which reduce the strength of the stereotypies by 50% over the observation period of 60 min. ED.Js of the second scoring 35 system are the doses which reduce the number of animals showing hyperactivity by 50% over the observation period of 60 min. The E13,0 were calculated from log dose- response curves by the rnethod of least squares from 4-6 dose levels with 6-8 animals per dose level.

B. In vitro test; Receptor binding assay The clinical efficacy of antipsychotic drugs has been shown to correlate with their ability to displace tritiated spiperone from preparations of dopamine receptors (Seeman, Biochem. Pharmacol. 26, 1741 (1977).

Method The method of Burt et al. (Proc.Nat-Acad.Sci. USA 72, 4655 (1975) was used. Male Spraque-Dawley rats weighing 150-200 g were decapitated, and their brains were rapidly removed. The striata were dissected, pooled and homogenized in 50 mM Tris- HCI buffer (pH 7.6). The membrane fraction was collected by centrifugation (48000 g for ten minutes), washed once with the buffer, and resuspended in 50 mM Tris-HCI (pH 7.6) containing 0. 1 % ascorbic 50 acid, 10 mM pargyline, 120 mM NaCl, 5 mM KCI, 2 mM CaC'2 and 1 MM MgCl2. The suspension was preincubated at 37 C for 10 minutes and then kept on ice until use.

The assays have been carried out using a cell harvester equipment. The incubations were made in quadruplicate, each well containing membrane suspension (2.5 mg/0. 5 MI), 3H spiperone (0.4 nM) and the test compound in a final volume of 0.5 ml. After incubation for 10 minutes at 37C, the contents of the wells were rapidly filtered and washed on Whatman GF/B filters using the Cell harvester. The specific binding was defined as the difference of ligand bound in the presence and in the absence of 1 tLIVI ( +)-butaclamol. The test results are expressed as IC50. The IC50 value given in ttM, indicates the concentration of the test substance which reduces the amount of specifically bound spiperone by 50%.

Test results The test results are given in the following table.

18 GB2153354A 18 Test compound In vivo In vitro Reduction of Reduction of Block of stereotypies hyperactivity 3 H-spiperone ED50 ED50 binding (pmolelkg i.p.) (ymolelkg i.p.) IC50 (juM) 5 Prior art compounds:

Br OCH3 Y CONHCH 10 6.5 0.86 1.57 OCH 3 c 2 H 5 (remoxipride, US patent 4 232 037) C] OH 15 / - \ CONHCH2 E 7N- 2.4 0.11 0.026 / CH3 C H c] 1 (a compound of 2 5 EP 60235) Compounds of the invention:

CH 3 CH 2 CH 2 OH 0-2 C). 10-3 _10-4 CONHCH2- 7N 26.1 24 CH 3 0 OCH 3 c H Br,_DH 30 CONHCH 2 N 2 3 4 1 4.210- 510- 1010 CH 30 OCH 3 c 2 H 5 c 2 H 5 OH 35 CONHCH JW 5.8110- 2 0.710-3 710- 4 CH 3 0 OCH 3 c H 19 GB 2 153 354A 19 Comments to the test results The compounds of this invention exhibit an antidoparnine activity superior to that of the tested compounds of the prior art both in vivo and in vitro. In their ability to inhibit the stereotypes induced by apomorphine in rats, the tested compounds of the invention are about 50-150 times more potent than the tested prior art compounds. Moreover, the difference between the 5

ED50 doses which block apomorphine-induced hyperactivity and the ED50 doses which block stereotypes is high, which indicates a highly selective action on specific dopamine neurons.

These properties could not be predicted from the properties of the prior art compounds.

The receptor binding studies in vitro confirm the high potency found in vivo of the compounds of the invention. The activity of the compounds of the invention on displacement of 10 31-1-spiperone from striatal preparations of the rat brain is very much higher than the activity of the tested prior art compounds.

Claims (27)

1. A compound of the formula R2 Z1 CONHCH 1 N 21 R3 Z9Z2 CH2 I wherein Z1, Z2 and Z3 are the same or different and each is selected from OH, OW, NH2, NR 4 4, 2, NHR SH, SR 4 and OR 4 wherein R' is formyl, acyl, alkoxycarbonyl or mono- or dialkylcarbamoyl and 25 R 4 is lower alkyl, R 2 is hydrogen, halogen, alkyl or lower trifluoroalkyl, R 3 is hydrogen, lower alkyl, alkenyl, alkynyl or phenyl, which phenyl may optionally be substituted by one or more of fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy and ethoxy in the ortho, meta or para positions, or may optionally be substituted by methylenedioxy; 30 provided that at least one of Z', Z2 and Z3 is a group OR 4 and further provided that when Z2 is OH or NI-12, Z1 is NR 4 4, 4 4 2, NHR SH, SR or OR or a physiologically acceptable salt or optical isomer thereof.

2 A compound according to claim 1 of the formula R 2 0A 1 ONHCH2,7E.

A

3 CH 2 -R 3 wherein A 3 is hydrogen or lower alkyl, R2 is hydrogen, halogen, lower alkyl or lower trifluoroalkyl, Z is selected from oxygen, sulphur, imino and alkylimino, A' is hydrogen, lower alkyl, formyl, acyl, alkoxyearbonyl or mono- or di- alkylcarbamoyl, A 2 is methyl or ethyl, R 3 is hydrogen, lower alkyl, alkenyl, alkynyl or phenyl, which phenyl may optionally be substituted by one or more of fluoro, chloro, bromo, trifl u oro methyl, methyl, ethyl, methoxy or ethoxy in the ortho, meta or para positions, or may optionally be substituted by methylenedioxy, 50 or a physiologically acceptable salt or optical isomer thereof. 3. A compound according to Claim 1 of the formula B OH CONHCH 2 N H3C0 OCH 3 cl 1 c 2 H 5 or CONHCH 2 Q- 11 H 3C0 OCH 3 HS GB 2 153 354A 20 or Br H CONHCH 2 5 CH30 OCH3 CH 2CH-CH 2 Br or ONHCH -j7) C 2 N 1. -//-\\ CH 3 0 OCH 3 L-2 -\_/ or H 5 c 2 DH CONHCH -' N 2 H 3 C0 OCH 3 c 2 H 5 or B -(CH2314-CH3 CONHCH 27 1 CH30 OCH 3 c 2 H 5

4. A process for producing a compound of formula 1 according to claim 1 which process 35 comprises reacting a compound of the formula R 2 z 1 _Xl CO 3 wherein -CO-Xl is a reactive group capable of reacting with an amino group under conditions suitable for formation of an amide moiety, with a compound of the formula H N-CH 2 2 'N' 1 CH 2 -R3 or a reactive derivative thereof and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt thereof and/or a substantially pure stereoisomer thereof.

5. A process for producing a compound of formula 1 according to claim 1, wherein ZI Z2 and Z3 are the same or different and selected from OH, OR' and OR 4 which process comprises 55 reacting a compound of the formula R2 z 1 -CONHCH --7 f N ZPZ 2 H, wherein ZI, Z2 and Z3 are the same or different and selected among OH, OR' and OR 4 with a compound of the formula 21 GB 2 153 354A 21 R 3_CH2 _X2 wherein X2 is a leaving group and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt thereof and/or a substantially pure stereoisomer 5 thereof.

6. A process for producing a compound of formula 1 according to claim 1 wherein one of Z1, Z2 and Z3 is NI-12 and the others are OH, OR', OR 4 or SR 4 comprising reducing a compound of formula 10 R2 z 1 -CONHCH 2 - 3 Z2 CH 2 -R 15 wherein one of ZI, Z2 and Z3 is N02 and the others are OH, OR', OR 4 or SR 4 and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt thereof and/or a substantially pure stereoisomer thereof.

7. A process for producing a compound of formula 1 according to claim 1 wherein ZI, Z2 20 and Z3 are the same or different and selected from OH, OR 4, NH2, NH 4, NHR 4, SH and SR 4 which process comprises reducing a compound of the formula R 2 z 1 CONHCH 2 EZ 3 COR wherein Z% Z2 and Z3 are the same or different and selected from OH, OR 4, NI-12, NH 4, NHR 4, 30 SH and SR 4 and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt thereof and/or a substantially pure stereoisomer thereof.

8. A process for producing a compound of formula 1 according to claim 1 wherein one or two Of ZI, Z2 and Z3 is a hydroxy group which process comprises removing a protecting group from a compound of the formula R 2 z 1 CONHCH J 7N 1 3 3 CH 2 -R wherein ZI, Z2 and Z3 are the same or different and are as defined in claim 1 or are suitably protected phenol groups corresponding to the hydroxy groups in the product and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt 45 thereof and/or a substantialy pure stereoisomer thereof.

9. A process for producing a compound of formula 1 according to claim 1 wherein R 2 is Br or Cl which process comprises reacting a compound of the formula zI CONHCH2--7N 1 3 3 CH 2 -R with a halogenating agent and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt thereof and/or a substantially pure stereoisomer thereof.

10. A process for producing a compound of formula 1 according to claim 1 wherein ZI and/or Z2 is OR 4, NR 4 or SR 4 which process comprises reacting a compound of the formula 60 2 22 GB 2 153 354A 22 R 2 z 1 CONHCH2--EN halo 5n 2 CH2-R wherein ZI and/or Z2 is OR 4, NR 4 or SR 4, halogen is Cl, Br or 1, with potassium hydroxide or 2 sodium hydroxide in aqueous media and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt thereof and/or a substantially pure stereoisomer 10 thereof.

11. A process for producing a compound of formula 1 according to claim 1 wherein R2 is hydrogen which process comprises catalytically hydrogenating a compound of the formula halogen Z1 - CONHCH2-17N 2 Cl H R 3 z 2 wherein halogen is Cl, Br or I and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt thereof and/or a substantially pure stereoisomer thereof.

12. A process for producing a compound of formula 1 according to claim 1 wherein at least one of V, Z2 and Z3 is OR' and any others of ZI, Z2 and Z3 are OR 4, NR 4 or SR 4 which process 25 2 comprises reacting a compound of the formula R2 z 1 2 -CONHCH p g3Z2 CH 2 R3 wherein any of Z1, Z2 and Z3 which is to become OR' in the compound of formula 1 is OH, with 35 a compound of the formula R 1-X3 wherein X3 is a leaving group and optionally thereafter converting the resultant compound of formula 1 to a physiologically acceptable salt thereof and/or a substantially pure stereoisomer 40 thereof.

13. A process according to any one of claims 4 to 12 for producing a compound according to claim 2 or claim 3.

14. A compound of the formula R2 z 1 CONHCH2-ZN 1 3 3 Z2 CH2-R wherein R 2 is hydrogen, halogen, lower alkyl or lower trifluoroalkyl, R 3 is hydrogen, lower alkyl, alkenyl, alkynyl or phenyl, which phenyl may optionally be substituted by one or more of fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy or ethoxy in the ortho, meta or para positions, or may optionally be substituted by methylenedioxy, Z', Z2 and Z3 are the same or 55 different and each is selected from OH, OR', NH2, NH 4 4, 4, 4 2, NHR SH, SR OR and a suitably protected phenol group wherein R' is a formyi, acyi, alkoxycarbonyl or mono- or dialkylcarba moyl and R 4 is lower alkyl, provided that at least one of Z', Z2 and Z3 is a protected phenol group and provided that at least one of Z', ZI and Z3 is a group OR 4 and further provided that when Z2 is OH or NI-12, Z1 is NR 4, SH, SR 4 or OR 4. 2

15. A compound according to claim 14 of the formula 23 GB 2 153 354A 23 R2 OA 1 ' CONHCH2-Z N 1 A3_ 2 CH 2 R3 wherein A3 is hydrogen or lower alkyl, 10 R2 is hydrogen, halogen, lower alkyl or.lower trifluoroalkyl, Z is selected from oxygen, sulphur, imino and alkylimino, A" is lower alkyl, A2 is methyl or ethyl, R3 is hydrogen, lower alky], alkenyl, alkynyl or phenyl, which phenyl may optionally be substituted by one or more of fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy and 15 ethoxy in the ortho, meta or para positions, or may optionally be substituted by methylenedioxy.

16. A compound of the formula R2 21 CODH z wherein Z1, Z2 and Z3 are the same or different and each is selected from OH, OR', NH2, NR2, NHRI, SH, SRI and OR' wherein RI is formyl, acyl, alkoxycarbonyl or mono- or dialkylcarbamoyl and RI is lower alkyl, R 2 is hydrogen, halogen, lower alkyl or lower trifluoroalkyl, provided that at least one of Z1, Z2 and Z3 is a group OR 4 and further provided that when Z2 is 30 OH or NH21 Z' is NR 4 4, 4 4.

2, NHR SH, SR or OR

17. A pharmaceutical preparation comprising as active ingredient a compound according to any of claims 1 to 3 or a physiologically acceptable salt or an optical isomer thereof.

18. A pharmaceutical preparation according to claim 17 in dosage unit form.

19. A pharmaceutical preparation according to claim 17 or claim 18 comprising the active 35 ingredient in association with a pharmaceutically acceptable carrier.

20. The use of a compound according to any of claims 1 to 3 or a physiologically acceptable salt thereof for the preparation of a pharmaceutical preparation comprising as an active ingredient an amount of said compound.

21. A compound according to any of claims 1 to 3 for use as a drug for the treatment of 40 diseases related to a dysfunction of the dopaminergic system.

22. A compound according to claim 1 and specifically named herein.

23. A compound according to claim 1 and substantially as hereinbefore described in any one of Examples 1 to 27.

24. A process for producing a compound according to claim 1 substantially as hereinbefore 45 described in any one of Examples 1 to 27.

25. A pharmaceutical composition according to claim 17 and substantially as hereinbefore described with reference to Example 28.

26. A compound according to any one of claims 14 to 16 and substantially as hereinbefore described with reference to any one of Examples 1 to

27.

Printed in the United Kingdom for Her Majesty's Stationery Office. Dd 8818935, 1985, 4235. Published at The Patent Office. 25 Southampton Buildings. London, WC2A l AY, from which copies may be obtained-